Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome

Abstract

Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.

Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

“…Further, one group criticized that the definition of the cardinal criterion aortic dilatation is based exclusively on Zscores which may, in their opinion, underestimate aortic involvement [Radonic et al, 2011]. Another analysis revealed that for the revised criteria, genotype information is essential for diagnosis or exclusion of MFS [Sheikhzadeh et al, 2011], emphasizing the importance of molecular genetic analysis in patients with suspected MFS.…”

Difficulties in diagnosing Marfan syndrome using current FBN1 databases

“…The Ghent II criteria highlight the importance of a FBN1 mutation test; for this reason, the focus on genetic testing has increased considerably when either diagnosing or excluding MFS. 4 With the introduction of next-generation sequencing, the sequencing price and the process time have been reduced considerably, and the amount of genetic sequencing data has been multiplied, resulting in an enormous amount of data that need to be evaluated. Moreover, access to genetic testing in the clinical setting is becoming more common and widespread, and the number of patients who are genetically tested is rapidly increasing.…”

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features

“…Since many patients carrying FBN1 mutations may develop classic MFS over time, genotype information is essential for the diagnosis or exclusion of MFS [Sheikhzadeh et al, 2012], despite the fact that knowledge about a specific FBN1 mutation seems to have little prognostic value for an individual patient and cannot reliably guide individual management [Hoffjan, 2012]. In our case, although the FBN1 C538P mutation seems not to favor the progression of aortic root dilatation, periodic echocardiograms should be performed to prevent the risk of aortic dissection in the follow-up.…”